Alzheimer's Disease is a common form of dementia associated with memory loss, intellectual function decline, depression, and disorientation. Alzheimer's Disease affects more than 5 million people in the United States and costs over $200 billion every year. (Alzheimer's Association, The Journal of the Alzheimer's Association (2012) 8: 131-168.) It is found in 13% of the population over the age of 65 and 45% of the population over the age of 85. (Alzheimer's Association, The Journal of the Alzheimer's Association (2012) 8: 131-168.) With a rapidly aging American population, prevalence of Alzheimer's Disease is expected to increase 2.5-fold to 13 million people in the United States in the next few decades. (Hebert et al., Arch Neurol (2003) 60: 1119-1122.) Alzheimer's Disease will continue to be a major and expensive health crisis.
Alzheimer's Disease is typified by increased deposition of amyloid beta plaques and neurofibrillary tangles in the brain. More than 95% of the cases are considered “sporadic” and affect individual older than 65 years of age (late-onset). These cases are distinguished from the rare, early-onset, genetically-linked cases where production and deposition of amyloid beta plaques is higher. (Bateman et al., Alzheimer's Res Ther. (2011) 3: 1-13). Individuals with late-onset Alzheimer's Disease produce amyloid beta plaques at a normal rate and level, but have a reduced ability to clear the amyloid beta plaques from the brain. (Mawuenyega, et al., Science (2010) 330: 1774.)
Apolipoprotein-E (apoE) is a cholesterol- and lipid-carrier that has been implicated in aging, atherosclerosis and several neurological diseases including Alzheimer Disease. (Mahley, et al., J Clin Invest (2006) 116: 1226-9, Thorngate, et al., Vasc Biol (2000) 20: 1939-45, Fullerton, et al., Exp Neurol (2001) 169: 13-22, Ji, et al., Neuroscience (2003) 122: 305-15, and Dergunov, et al., Biochemistry (Mosc) (2006) 71: 707-12.) ApoE genotype is the biggest risk factor for Alzheimer's Disease and may account for 60%-90% of the genetic variance associated with Alzheimer's Disease. (Raber, et al., Neurobiol Aging (2004) 25: 641-50.)
There are three common isoforms (alleles) of apoE in humans: apoE2, apoE3, and apoE4—which contribute to the pleiotropic effects observed in human cognition and neurodegenerative diseases. (Bales, et al., Proc Natl Acad Sci USA (1999) 96: 15233-3, Holtzman, et al., J Clin Invest (1999) 103: 15-21.) The risk for Alzheimer's Disease is two- and seven-fold higher in subjects that are heterozygous and homozygous, respectively, for apoE4. (Corder, et al., Science (1993) 261:921-3.) The age of disease onset is also accelerated by 6 years-8 years for each inherited copy of apoE4. (Corder, et al.) Several groups consider the apoE4 allele to be detrimental because the apoE4 protein aggregate with amyloid beta plaques more readily than other alleles and apoE4 protein is less effective at clearing the amyloid beta plaques from the brain (Tokuda, et al., Biochem J (2000) 348: 359-65, Castellano, et al., Sci Transl Med (2011) 3:895-7, and Buttini, et al., Neuroscience (2000) 97:207-10.).
These and other neurodegenerative effects have led some to conclude that apoE4 protein behaves like a “dominant-negative mutant,” is a “neglected opportunity” for treatment of Alzheimer's Disease. (Michaelson, D. M. (2014) Alzheimers Dement 10:861-868.) Thus, there is a strong interest in the biomedical community to find therapies that can reduce apoE levels. Several animal studies clearly demonstrated that reduction of apoE4 and apoE3 reduce toxic amyloid accumulation. (Kim, J., et al. J Neurosci. (2011) 31:18007-18012; Bien-Ly, N., et al. J Neurosci. (2012) 32:4803-4811.)
High levels of low-density lipoprotein (LDL) and low levels of high-density lipoprotein (HDL) cholesterols are considered to be strong risk factors for cardiovascular diseases. The low density lipoprotein (LDL) receptor-related protein (LDLR) is a ubiquitously expressed endocytic receptor that binds a diverse group of ligands, including lipoproteins, lipoprotein lipase, proteases, protease inhibitors and protease:inhibitor complexes, bacterial toxins, viruses, and lactoferrin. Some of these macromolecules compete with each other for a common site on LDLR, while others bind to independent sites.
The gene encoding LDLR is an essential gene, because it participates in a wide range of biological processes. LDLR is a cell surface protein that plays an important role in mediating the removal of LDL cholesterol particles from the blood circulation (Brown M S and Goldstein J L. Science. (1986) 232(4746):34-47). Because LDL is causally associated with cardiovascular diseases, various strategies to decrease LDL cholesterols have been pursued for drug development.
Interestingly, apoE is implicated in atherosclerosis and Alzheimer's Disease (Mahley, et al., J Clin Invest (2006) 116: 1226-9.). In the brain, LDL receptor is the major apoE receptor. It has been demonstrated that reduction of apoE protein levels by overexpressing LDLR can dramatically inhibits toxic amyloid accumulation in the brains of a mouse model of Alzheimer's disease (Kim J, et al. Neuron (2009) 64:632-644). The finding that reduction of apoE levels can dramatically inhibit toxic amyloid accumulation is also supported in subsequent studies that genetically or pharmacologically inhibited apoE in the brain (Kim J, et al. J Neurosci (2011) 31:18007-18012; Kim J, et al. J Exp Med (2012) 209:2149-2156; Liao F, et al. J Neurosci (2014) 34:7281-7292.)
Like LDLR, the AbcA1 protein also plays a key role in regulating cholesterol in biological systems. HDL functions to transport cholesterol from peripheral cells to the liver by reverse cholesterol transport, a pathway that may protect against atherosclerosis by clearing excess cholesterol from arterial cells. A cellular ATP-binding cassette transporter (Abc) called AbcA1 mediates the first step of reverse cholesterol transport, the transfer of cellular cholesterol and phospholipids to lipid-poor apolipoproteins. Mutations in AbcA1 cause Tangier Disease (TD), a severe HDL deficiency syndrome characterized by accumulation of cholesterol in tissue macrophages and prevalent atherosclerosis.
Studies of TD heterozygotes revealed that AbcA1 activity is a major determinant of plasma HDL levels. Drugs that induce AbcA1 in mice increase clearance of cholesterol from tissues and inhibit intestinal absorption of dietary cholesterol. Multiple factors related to lipid metabolism and other processes modulate the tissue-specific expression of AbcA1. Therefore, as the primary gatekeeper for eliminating tissue cholesterol, AbcA1 has a major impact on cellular and whole body cholesterol metabolism and plays an important role in protecting against cardiovascular disease and Alzheimer's disease. (Koldamova R, et al. Neurobiol Dis (2014) 72:13-21; Liu Y and Tang C. Biochem Biophys Acta (2012) 1821:522-529.)
Since the American population is aging, and the percentage of American people with Alzheimer's Disease is expected to increase, there is the urgent need to further develop small organic molecules that can be easily administered to prevent, slow or stop the progression of the disease. Organic molecules that control the biological amounts of apoE, LDLR, and/or AbcA1 produced in mammalian systems would be of interest in light of the prior art.
The “Background of the Invention” section is provided for background information only, and is not an admission that any subject matter or references described in this section constitutes prior art to the present disclosure.